With the advance of the aging society, the number of patients with Alzheimer-type dementia has increased in recent years, which has become a social problem.
The onset of Alzheimer-type dementia is considered to be deeply associated with the process of aggregation and accumulation following the enhanced production or reduced degradation of amyloid β proteins (hereinafter, referred to as Aβ), which are the main constituents of senile plaques characteristic of the brains of the patients.
This Aβ is composed of 40 to 42/43 amino acids rich in hydrophobic amino acids and produced from its precursor, amyloid precursor protein (hereinafter, referred to as APP) by hydrolytic cleavage. Moreover, APP is found as three isoforms: APP composed of 695 amino acids (hereinafter, referred to as APP695), APP composed of 751 amino acids (hereinafter, referred to as APP751), and APP composed of 770 amino acids (hereinafter, referred to as APP770).
The Aβ production from APP is performed through two-stage reaction, the first stage of which is β-secretase cleavage at the N-terminus in the extracellular domain and the second stage of which is γ-secretase cleavage at the C-terminus in the transmembrane region.
The previous findings have suggested that the cleavage at the second stage occurs at the C-terminal γ site of Aβ. However, according to the recent findings, it has been reported that the γ-secretase cleavage occurs nearer the cytoplasm, i.e., at the ε site (for APP770, Thr719-Leu720 or Leu720-Val721) 5 to 10 amino acid residues further downstream (C-terminal direction) from the γ site.
As currently known γ-secretase inhibitors, there have been reported, for example, a peptide mimetic DFK-167 based on the γ site of the substrate APP on which the enzyme acts (Non-Patent Document 1), a compound L-685,458 screened from among known inhibitors (Non-Patent Document 2), JLK-6 (Non-Patent Document 3), and a peptide mimetic based on the ε site (Patent Document 1).
However, the DFK-167 is an inhibitor designed for the γ site. Therefore, its design target and structure are totally different from those completed based on the recently reported findings about the ε site. Thus, the DFK-167 has the problem of an insufficient effect as an inhibitor.
Moreover, the L-685,458 and the α-chymotrypsin inhibitor JLK-6, which have been prepared during the course of the development of therapeutic drugs for AIDS, are not originally compounds developed as inhibitors specific to γ-secretase for Aβ production from APP. Therefore, they are insufficiently effective for the target tissue and have the problem that their nonspecific inhibition of γ-secretase activities might induce severe side effects such as induction of malignant transformation.
Furthermore, Patent Document 1 discloses a Thr-Leu-Val-Met-type compound as the peptide mimetic based on the ε site. However, this compound has the problem of an insufficient effect as an inhibitor. Examples of the document disclose a Thr-Leu-Val-Met-type compound (1′a) having a t-butyl-etherified hydroxyl group of Thr. However, this compound was merely a synthetic intermediate in a sense and was incomplete as the Thr-Leu-Val-Met-type compound.
In addition, a Thr-Leu-Val-Met-type compound having an unprotected hydroxyl group of Thr and the specific γ-secretase inhibitory effect of the compound have been unknown so far.    Patent Document 1: WO03/091278    Non-Patent Document 1: J. Med. Chem., 1998, 41 (1), 6-9    Non-Patent Document 2: Biochemistry, 2000, 39 (30), 8698-8704    Non-Patent Document 3: J. Biol. Chem., 1979, 254 (10), 4027-4032